Investigators of the Indiana Alcohol Research Center are world leaders in the development and characterization of selected lines of rodents for studies on alcohol preference and craving, the application of the alcohol clamp to permit precise control of blood alcohol levels, and the identification and study of genetic variants which influence responses to alcohol and risk of alcoholism. In the next period of support, we will 1) expand existing educational, collaborative research, and outreach activities on alcoholism for health and legal professionals around the world;2) continue selective breeding and provide rat (P/NP, HAD/LAD) and mouse (HAP/LAP) lines for Center investigators;3) provide genomic (expression profiling, real-time PCR confirmation of changes in mRNAs, high density SNP genotyping /haplotyping, ADH and ALDH genotyping) expertise for Center investigators and collaborators;4) correlate responses to alcohol, frontal lobe fMRI activity, pharmacokinetics, and factors that predict the risk for future alcoholism in subjects with family history of alcoholism and risk genotypes at the GABRA2 and ADH4 loci;5) examine mRNA expression profiles in the ventral tegmentum and accumbens-shell regions of P/NP and HAD/LAD rats during alcohol exposure paradigms;6) examine associations between high alcohol preference and sensitivity to nicotine and cocaine, and the effects of these drugs on alcohol responses;7) examine spatial and termporal patterns of embryonic gene expression in alcohol-exposed embryos, and relevant transcriptional mechanisms for these changes;8) support innovative pilot projects linked to the themes of the Center: functional brain imaging, 3 dimensional analysis of alcohol teratogenesis, genetics of response to naltrexone and of craving for alcohol, and alcohol teratogenesis in zebrafish;and 9) provide a rich environment for the training of undergraduate and graduate students, postdoctoral fellows, and visiting scientists. As a well-established Center, we will continue to mentor younger faculty for leadership roles in the Center and in the broader alcoholism research field. Public Health Relevance: These studies will provide better understanding of how genetic backgrounds affect responses to alcohol and other drugs of abuse, explanations for the sensitivity of the developing fetus to alcohol, and will seek to expand knowledge about alcoholism among health professionals and legal authorities, both in the US and around the world.